Cancer of the colon and rectum is the third most frequently diagnosed cancer in the United States and accounts for the second largest number of cancer deaths. Even with the widespread occurrence of colorectal cancer, we only know how a few key genes, primarily associated with familial forms of colorectal cancer, are involved in its initiation and progression. The major goals of this research are to study the mode of susceptibility to the sporadic development of colorectal cancer and to identify regions of the genome that modulate this susceptibility. They will use an innovative approach combining the power of mouse embryological manipulation and genetics to achieve these goals. These goals will be pursued in two specific aims. The first specific aim is to address the mode by which resistance/susceptibility to colorectal cancer development is determined using a carcinogen-induced mouse model of colorectal cancer. They will utilize chimeras, an analysis of crypt architecture, and immunodeficient mice to pursue this aim. The second specific aim will be to survey several inbred mouse strains to gather preliminary data on the variability of colorectal cancer resistance/ susceptibility genes and to perform a serial backcross experiment to localize subsets of these genes from two strains of mice. Having a better understanding of how genetic factors effect the development of cancer will greatly aid our prognostic predictions. Additionally, having susceptibility markers to sporadic cases of colorectal cancer will permit us to better evaluate the interaction of genetics and the environment in the initiation and progression of colorectal cancer.